Summary: One of the major downsides of improved economy and prosperity is the rise of diabetes-mellitus. Sedentary life-style and high calorie diet are implicated in the rise of diabetes. Patients with diabetes are at high risk of developing cardiomyopathy and heart failure (HF). Such patients also experience worst clinical outcome following, hypertension, myocardial infarction and cardiac surgery. At the cellular level, increased inflammation, insulin-resistance, cardiac hypertrophy and fibrosis are considered hallmarks of diabetic cardiomyopathy. However, the underlying mechanism of this disease process is not yet completely understood, and no targeted therapy is available to treat diabetic cardiomyopathy. New approaches are needed to understand the mechanism behind this disease, and to identify new therapeutic strategies to protect the heart from descending to failure post diabetic cardiomyopathy. My laboratory has specific interests in sirtuins (SIRTs), which are emerging as key regulators of myriad of biological functions, spanning from cell growth, differentiation to longevity. Recent work from our laboratory has identified SIRT6, as an endogenous negative regulator of cardiac hypertrophy. In diabetic hearts, we found that SIRT6 levels were drastically reduced; and this was paralleled with increased expression of activators of fibrosis, inflammasome formation and insulin-resistance. We also found that SIRT6 deficiency leads to decreased expression of genes needed to maintain structure and function of mitochondria. These findings led us to hypothesize that decreased SIRT6 levels contribute to the evolution of diabetic cardiomyopathy and subsequent HF. Therefore, a diabetic heart can be protected from descending to HF by augmenting cardiac SIRT6 levels. We will test this hypothesis in the following three aims: (Aim 1) Study whether loss of SIRT6 contributes to pathologic changes associated with the evolution of diabetic cardiomyopathy, and whether SIRT6 overexpressing transgenic mice are protected from developing HF post diabetes. (Aim 2) Study the underlying mechanism of SIRT6 deficiency during diabetes, and the mechanism through which SIRT6 maintains mitochondrial health and protects the heart from developing the disease. (Aim 3) Study whether pharmacological targeting of SIRT6 can protect the heart from developing diabetic cardiomyopathy and HF. The knowledge gained from completing these aims will be extremely important to understand what roles sirtuins play in pathogenesis of diabetic cardiomyopathy, and that could be pertinent to developing new therapies for treatment of HF in diabetic patients.